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THE MORGAN WELCH INFLAMMATORY BREAST CANCER RESEARCH PROGRAM AND CLINIC
Annual Report for Fiscal Year 2012
2
Naoto T. Ueno, MD, PhD
Execu ve Director
Vicente Valero, MD
Clinical Research Director
Savitri Krishnamurthy, MD
Core Leader
Wei Yang, MBBS, FRCP
Core Leader
Danielle M. Walsh, MBA
Program Manager
Wendy Woodward, MD, PhD
Deputy Director
James Reuben, PhD
Execu ve Commi ee Member
Anthony Lucci, MD
Core Leader
Randa A. El‐Zein, MD, PhD
Core Leader
Tom Buchholz, MD
Special Advisor
Executive and Core Leaders
3
Contents
Overview ........................................................................................................................................................................... 4
Program Leadership .......................................................................................................................................................... 6
Financial Review ................................................................................................................................................................ 7
Philanthropy ...................................................................................................................................................................... 8
Clinical Research and Opera ons .................................................................................................................................... 10
Core Program Research Updates .................................................................................................................................... 12
Diagnos c Radiology: Wei Yang MBBS, FRCP .................................................................................................... 12
Epidemiology: Randa A. El‐Zein, MD, PhD ........................................................................................................ 12
Breast Medical Oncology: Naoto T. Ueno, MD, PhD ......................................................................................... 14
Surgical Oncology: Anthony Lucci, MD .............................................................................................................. 17
Radia on Oncology and Stem Cell Biology: Wendy Woodward, MD, PhD ....................................................... 18
Pathology: Savitri Krishnamurthy, MD ............................................................................................................... 19
Immunology and Hematopathology: James Reuben, PhD ................................................................................ 21
Breast Medical Oncology—Research: Chandra Bartholomeusz, PhD ............................................................... 22
Surgical Oncology—Research: Balraj Singh, PhD .............................................................................................. 22
Breast Medical Oncology—Research: Bedrich Eckhardt, PhD .......................................................................... 23
Program Outreach ........................................................................................................................................................... 24
THE MORGAN WELCH INFLAMMATORY BREAST CANCER RESEARCH PROGRAM AND CLINIC
Annual Report
for Fiscal Year 2012
4
Overview
T he University of Texas MD Anderson Cancer Center
Morgan Welch Inflammatory Breast Cancer Research
Program and Clinic is a unique model of mul ‐disciplinary care and
research focused on understanding, preven ng and trea ng
inflammatory breast cancer (IBC). While IBC is considered rare,
a ribu ng to only 2‐5% of all breast cancers, its aggressive nature
makes it the deadliest, with only a 35‐40% 5‐year survival rate. In
fact, death from IBC is dispropor onate when compared to all
breast cancers, resul ng in up to 10% of all breast cancer deaths.
Our mul disciplinary program is focused on developing tools for
diagnosis, iden fying therapeu c approaches specifically for
treatment of IBC, understanding and preven ng metastases,
enhancing imaging approaches to assist in detec ng the disease
and evalua ng the effec veness of treatment for IBC pa ents. Our
ul mate goal is to improve survival of IBC pa ents.
Over the past year, the Morgan Welch IBC Program has strived to
progress into a period of strategic growth in pa ent care, basic
and transla onal research, and in outreach. To accomplish this we
have realigned our purpose and budget with clear mission, vision
and defined goals for achievement.
Our mission is to reduce the suffering of IBC pa ents through
transla onal research–driven, clinical medicine.
Our vision is to be a world premier IBC research group in disease
preven on, in developing innova ve molecular biomarkers and
targeted therapy based on hypothesis‐driven transla onal/clinical
research, and in nurturing a new genera on of oncology
inves gators.
To reduce the suffering of IBC
pa ents through transla onal
research–driven, clinical medicine
OURMISSION
To be a world premier IBC research
group in disease preven on, in
developing innova ve molecular
biomarkers and targeted therapy
based on hypothesis‐driven
transla onal/clinical research, and
in nurturing a new genera on
oncology inves gators.
OURVISION
5
B ased on the shared mission and vision, we defined our Program goals and aligned resources and effort to
answer the following targeted ques ons over three years beginning in September 2011.
Further, we iden fied the following innova ons or changes as necessary to enhance our ability to answer the three
ques ons above.
Through a concerted effort by all members of the program and through new collabora ons, the Morgan Welch IBC
Program is commi ed to making breakthroughs in the understanding of IBC and how we can prevent, diagnose and
treat new or metasta c disease. In June of 2012, members of the Program a ended a team‐building workshop to
understand and evaluate our mul ‐disciplinary approach and to explore areas of opportunity for collabora on. From
this workshop , we have iden fied 3 new working groups and topics of interest. Moreover, the workshop increased
synergy between the disciplines and among the research staff and faculty. It was also a chance for the team to hold
each other accountable to the mission, vision and goals of the Program.
How can we dis nguish IBC from non‐IBC at the molecular level that will lead to universal diagnos c criteria?
What are the IBC unique e ologies that can be developed as IBC‐specific targets?
What are the risk factors for a development of IBC?
Development of molecular epidemiology
Development of a large clinical and biomarker database
Development of reliable IBC animal models
Well‐defined collabora on strategies with a clear plan
Development of theme‐focused research planning
Development of novel IBC clinical trials that include an extensive transla onal research component
6
Program Leadership
L eadership of the Morgan Welch IBC Program transi oned in early FY12 as Dr. Naoto T. Ueno was appointed
Execu ve Director and Dr. Wendy Woodward as Deputy Director. Dr. Vicente Valero con nues to serve as
Clinical Research Director. Program Core Leaders represent the mul ple disciplines that comprise the Morgan Welch
Program and oversee the strategic interests of the Program while the Execu ve Commi ee, a sub‐commi ee of Core
Leaders, addresses daily opera ons. Together with the Execu ve Commi ee and Core Leaders of the Program, Drs.
Ueno, Woodward and Valero are commi ed to building upon the success of the mul ‐disciplinary IBC clinic and
laboratory.
Naoto T. Ueno, MD, PhD
Execu ve Director
Wendy Woodward, MD, PhD
Deputy Director
James Reuben, PhD
Execu ve Commi ee
Vicente Valero, MD
Clinical Research Director
Savitri Krishnamurthy, MD
Core Leader
Anthony Lucci, MD
Core Leader
Randa El‐Zein, MD, PhD
Core Leader
Wei Yang, MD
Core Leader
Tom Buchholz, MD
Core Leader
Danielle M. Walsh, MBA
Execu ve Commi ee
7
T he Morgan Welch IBC Research Program and Clinic was formally established in September 2007 with a
$4 million State appropria on en tled “Rare and Aggressive Breast Cancer Research”. Monies from the
State of Texas, renewed in 2009 and 2011, have allowed us to build the infrastructure to support a dedicated
clinical and transla onal research team and have funded research projects in the laboratory and in the clinic, with
direct impact to our pa ents.
FY12 has brought new challenges to the Program as we faced a reduc on in appropria ons via the State of Texas Rare
and Aggressive Cancer program. We took this as an opportunity to be er align resources towards our defined
common goals as the 20% reduc on in appropria ons funding deemed it cri cal for us to become more efficient and
effec ve in our use of resources. Our inten ons with the alloca on of funds were to alleviate the financial burden of
projects and programs that did not support IBC goals and reallocate funds to new collabora ons and seed projects.
Moreover, we felt an urgent need to iden fy and secure other funding to support the Program so that we can leverage
the state funds and other resources more effec vely. The table below reflects expenditures of the Program in 2012,
including clinical research and donor funds. These figures do not include individual principal inves gator sponsored
project funds.
Financial Review
State Appropria ons
Sponsored Projects
Donor Funds Clinical Trials Total
Personnel $1,373,935.44 $2,842.49 $27,317.41 $184,433.06 $1,588,528.40
Non‐Personnel $239,759.18 $13,541.16 $34,577.57 $67,287.25 $355,165.16
Total Expenditures
$1,613,694.62 $16,383.65 $61,894.98 $251,720.31 $1,943,693.56
8
W e are grateful for the generous
philanthropy bestowed upon the program
in FY12. The Zeta Tau Houston Alpha Alumnae Associa on, in
addi on to their already established endowment fund, made
a gi in direct support of IBC research. This year we have
launched the First Annual Zeta Tau Alpha Houston Alumnae
Associa on Fellowship in Inflammatory Breast Cancer
Research. The call for abstracts, eligibility requirements and
judging criteria were designed by the Morgan Welch IBC
Program Execu ve Commi ee. The goal of the awards is to
honor and recognize efforts with excep onal quality of IBC
research and high impact (or poten al impact) for our IBC
pa ents. Further the monetary award will provide a means
for the individual to travel to a na onal or interna onal
mee ng to present their unique research and share their
knowledge of IBC. The commitment from Zeta Tau Alpha
Houston Alumnae Associa on has made this legacy award
possible and we are ever grateful for the con nued
generosity and support.
In October 2011, Team Karen hosted their 3rd Annual Team
Karen 10K trail run and Kids K Bike Race at Reveille Peak
Ranch in Burnet, Texas. Mr. and Mrs. David and Karen
Co rell have long been supporters of IBC research through
the Morgan Welch IBC Program and we are grateful for their
endeavors to raise awareness of IBC in a fun and family‐
friendly way. The funds raised through the Karen Co rell and
Team Karen Inflammatory Breast Cancer Fund are being used
as seed funding for new research projects. As such, a project led by Dr. Ricardo Alvarez, assistant professor in Breast
Medical Oncology and physician in the Morgan Welch IBC Clinic, was iden fied to be the first such funded project.
Under the mentorship of Dr. Naoto Ueno, Dr. Alvarez has begun the preclinical and cell culture analysis of the drug
siltuximab, the first of two aims in his project en tled “Role of IL6 in IBC preclinical model”. The second aim of this
study is to develop an animal model based on the preliminary results.
Throughout FY12, The IBC Network Founda on ac vely hosted “Hunt for Hope” events across the country to raise
money for IBC research. The goal of the founda on is to directly fund important projects that may be unique and/or
limited to types of metasta c disease and thus less likely to be supported through federal funding mechanisms. In
Philanthropy
The Zeta Tau Alpha Founda on has established an
endowment through the Morgan Welch IBC
Program to fund a fellowship in inflammatory
breast cancer research . Winners of the First
Annual Zeta Tau Alpha Houston Alumnae
Associa on Fellowship in Inflammatory Breast
Cancer Research announced on October 5, 2012
were Lara Carolina Alvarez de Lacerda, PhD and
Gary Walker, MD, MPH.
ZETATAUALPHAHOUSTONALUMNAEASSOCIATION
9
April of this year, the Founda on presented to Dr. Wendy Woodward, associate professor in Radia on Oncology and
Deputy Director of the Morgan Welch IBC Program, a check to fund the Lori Grennan Pleural Effusion Study. This
unique study will determine if we can reprogram cancer cells to stop dividing and reduce the symptoms of fluid in the
lungs caused by metasta c breast cancer. This somewhat unusual outcome of breast cancer impacts many of our IBC
pa ents and, to date, placing a tube to remove this fluid is the only specific treatment. Through our laboratory studies
of these fluids we have learned they contain cancer stem cells that con nually renew cancer cells as they are removed.
We hope this trial of reprogramming cancer cells and hal ng this renewal with valproic acid will be a stepping stone to
novel approaches to treat and cure metasta c disease in many organs. This trial would not have been possible without
the generosity of the IBC Network Founda on and we are thankful to have the opportunity to bring this novel approach
to our pa ents.
We would also like to extend apprecia on to individuals who donated me or money to our Program. Your
though ulness and generosity foster support for inflammatory breast cancer research in numerous ways.
We are eternally grateful and thank you for thinking of our cause.
10
Clinical Research and Operations
P a ent care is the heart of our Program as we strive to reduce the suffering of pa ents with IBC. The lack of
exis ng standard of therapy for this pa ent popula on and the dispropor onate number of pa ents dying
from this disease necessitates that we iden fy novel approaches to bring advancement in therapy op ons. For this
reason, clinical trials are an integral part of our treatment approach for both newly diagnosed and metasta c disease.
During FY12, the Program’s clinical trial por olio was comprised of 10 ac ve trials, with 3 studies comple ng
enrollment, 3 new trials ac va ng and 4 new studies in development. Our landmark interna onal IBC pa ent registry
accrued a total of 59 new pa ents. This par cular protocol is important as it is the founda on for our basic and
transla onal research—providing the precious pa ent ssue and epidemiological data that will lead our understanding
of the disease. In addi on to the registry study, 41 pa ents par cipated in clinical studies targeted to IBC. Pa ent
par cipa on in these studies is important as we seek to define a new standard of treatment for our pa ents and
improve their outcomes.
Protocol
Number Protocol Title
Principal
Inves gator
Ac va on
Date
Target
Accrual
2008‐0372 Phase II study of Panitumumab, Nab‐paclitaxel, and carbopla n for pa ents with primary IBC without HER2
‐overexpression Ueno 11/1/2010 40
NSABPFB‐7
A Phase II randomized Clinical Trial Evalua ng Neoadjuvant Therapy Regimens with Weekly Paclitaxel and
Nera nib or Trastuzumab or Nera nib and Trastuzumab Followed by Doxorubicin and Cyclophosphamide
with Postopera ve Trastuzumab in Women with Locally Advanced HER2 Posi ve Breast Cancer
Valero 6/13/2011 10
2010‐0696
A phase I/II study to evaluate the safety, tolerability, and preliminary efficacy of KW‐2450 in combina on
with lapa nib and letrozole in subjects with advanced or metasta c breast cancer whose tumor over‐
express HER2
Ueno 6/13/2011 10
2010‐0683
OAM4861g A randomized, phase II, mul center, double‐blind, placebo‐controlled study evalua ng the
safety and efficacy of MATMAb in combina on with Paclitaxel in pa ents with metasta c, triple‐nega ve
breast cancer
Valero 9/21/2011 15
2010‐0296 A Phase II Study of TKI258 (Dovi nib Lactate) as Salvage Therapy in Pa ents with First Local or Distant
Relapse HER2‐nega ve Inflammatory Breast Cancer (IBC) (up to 2 prior therapy) Alvarez 1/27/2012 33
2010‐0842 A phase I/II Study of En nostat and Lapa nib in Pa ents with HER2‐Posi ve Metasta c Breast Cancer in
Whom Trastuzumab has Failed Ueno 1/10/2012 70
2006‐1072 IBC Interna onal Pa ent Registry Ueno 4/17/2007 500
LAB08‐0199 Reac va on of Epstein‐Barr Virus in Pa ents with Inflammatory Breast Cancer Reuben 160
LAB04‐0657 A Model of COX‐2 Mediated bone Metastasis in Human Breast Cancer to include IBC cohort I Lucci 800
LAB04‐0698 Pilot Study: Correla on of Circula ng tumor cells and COX‐2 Expression in Primary Breast Cancer metasta‐
sis To include IBC cohort I Lucci 800
2007‐0818 A phase II study of neoadjuvant Lapa nib plus chemotherapy (sequen al FEC75 and Paclitaxel) in women
with inflammatory breast cancer whose tumors overexpress ErbB@ (Her2/neu) Alvarez
CNPE:
12/30/2011
2007‐0448 A Randomized, Mul center, Phase III Study Comparing the Combina on of Pazopanib and Lapa nib versus
Lapa nib Monotherapy in Pa ents with ErbB2 over‐expressing Inflammatory Breast Cancer Alvarez
Terminated:
11/2011
2007‐0766 A phase I‐II study of R115777 (Tipifarnib, Zarnestra) plus sequen al weekly paclitaxel followed by dose‐
sense doxorubicin and cyclophosphamide in pa ents with stage IIB‐IIIC breast cancer Her2(‐) Valero
CNPE:
12/27/10
11
The Morgan Welch Inflammatory Breast Clinic within the Nellie
B. Connally Breast Center at MD Anderson was established
based on our commitment to provide pa ent‐centered team
care incorpora ng all of the cri cal clinical team members from
each discipline into one IBC team. This mul ‐disciplinary team
medicine approach, combined with the broad experience and
exper se that only comes from seeing and trea ng hundreds
of pa ents with this rare disease, is cri cal to the care and
outcomes for our pa ents. Our Board Cer fied clinical team
consists of four breast medical oncologists, three radia on
oncologists, three surgical oncologists, three pathologists, and
two breast imaging radiologists. Further the clinic is supported
by dedicated advanced prac ce nurses, registered nurses,
research nurses, clinical studies coordinators and research
technicians. We are not only commi ed to research and
treatment of inflammatory breast cancer, we specialize in it.
We work together to provide the best care to our pa ents and
excel in providing the best experience for them.
In addi on to our long history trea ng IBC at MD Anderson
Cancer Center, our clinic has treated hundreds more IBC
pa ents in just the last 5 years. Before the clinic opened, MD
Anderson was seeing on average 10‐15 IBC pa ents per year.
This has since increased to 85‐100 pa ents per year, with more
than 750 pa ents being seen in the Morgan Welch Clinic since
2006.
Our IBC clinic is supported by world‐class dedicated researchers who work together (team science) to bring new
therapies to pa ents and to solve the mystery of this deadly disease. To aid in our understanding of this virulent
disease and to improve collabora on and synergy among IBC inves gators, we opened the first comprehensive
research laboratory dedicated to IBC in late 2009. The team science model encourages constant communica on and
collabora on and allows our researchers to leverage shared resources. Moreover, the state‐of‐the‐art facility provides
a centralized core for the IBC biorepository, a collec on of ssue and serum from our own IBC pa ents and partner
centers from around the world.
The Morgan Welch IBC Research Program and Clinic is unique in its comprehensive approach to the disease. From
bench to bedside, from early diagnosis to preven on of metastasis, we are working together to bring a new future to
the women and men who face this disease.
12
Core Program Research Updates
I n addi on to pa ent care, the Morgan Welch IBC Program is commi ed to research at the basic and transla onal
levels. We recognize that to be able to improve the lives of our pa ents through be er preven on or diagnos c
strategies and to be able to offer more effec ves therapies, we need to study IBC and its environment at a molecular
and genomic level. Moreover, by understanding the mechanisms for metastasis, we may be er be able to inhibit
disease progression, necessary for improving survivability. Following are updates from our key program leaders and
other projects in IBC.
D R W Y , MBBS, FRCP Current Work: 1. Mul modality Imaging Staging Work‐up for all newly diagnosed IBC pa ents to include same day mammography,
US with protocol biopsy (as necessary), and MRI
2. Collec on of tumor samples for tumor bank and related op cal imaging protocols (Collabora on with DiHua Yu,
MD, PhD and Rice Bioengineering on Komen Promise Grant)
3. Response monitoring with MRI and PET‐CT
a Assessment of Residual Disease (Breast)
b Assessment of Residual Disease (Axilla)
c Imaging Predictors (Survival)
Opportuni es: 1. We should work with Pathology (Savitri Krishnamurthy) and new technology companies to inves gate the
feasibility of assessment core samples for tumor cellularity (virgin tumor).
2. Explore opportuni es to assess func onal imaging parameters with genomic informa on on collected tumor
samples.
E R A. E ‐Z , MD, P D
The goal of this core is to provide the epidemiological support for the Morgan Welch Inflammatory Breast Cancer
Research Program. The epidemiological component includes two important areas, namely: i) Tradi onal Epidemiology
and ii) Molecular Epidemiology. During the past year and through support from the Morgan Welch Inflammatory
Breast Cancer Research Program, we were able to achieve the following:
Epidemiological Achievements
To date, a total number of 235 pa ents have been enrolled into the IBC Registry.
13
The risk factor ques onnaire that includes socio‐demographic
informa on, reproduc ve, medical, family history, breast health
history as well as detailed informa on on tobacco, alcohol use,
occupa onal and environmental exposures, was completed on
100 pa ents [some of whom were enrolled into the study the
previous year but did not complete the risk factor
ques onnaire]. Figure 1 summarizes selected demographic
characteris cs of the study popula on and Table 1 represents
the selected risk factors associated with the disease.
Approximately 37 new pa ents were enrolled. A new database
was successfully developed. The database can be linked to the
clinical and ssue specimens to facilitate collabora ons among
the program inves gators. In addi on, the risk factor
ques onnaire and database have been adapted for use by the
other partner sites.
Molecular Epidemiological Achievements
On the molecular level, li le is known about the underlying
molecular altera ons involved in the pathogenesis of IBC. It has
been suggested that the mechanisms for the induc on of
chromosomal damage are similar in different ssues, and
therefore the extent of chromosomal damage evaluated in
lymphocytes reflects damage in cancer‐prone ssues. To date,
we have approximately 160 pa ents with completed clinical and
risk factor ques onnaire on who blood was obtained for the
molecular epidemiological studies.
We conducted a case‐control study on IBC
pa ents and age and ethnicity matched controls
to assess the level of overall gene c instability in
blood lymphocytes using the mul ‐endpoint
cytokinesis‐block micronucleus assay, an
established biomarker for DNA damage and
genomic instability. All chromosome damage
endpoints were significantly higher among the IBC
cases as compared to controls with a mean + SE =
5.4+ 0.15 vs.1.7+ 0.12; 8.2+ 0.14 vs. 1.1+ 0.12;
1.3+ 0.1 vs. 0.4+ 0.1; p<0.0001 for micronuclei,
nuclear bridges and nuclear buds endpoints
respec vely, Figure 2.
We furthered our inves ga on to compare the
level of gene c instability in IBC vs. non IBC
pa ents and to iden fy non‐random events associated with the disease. We used G‐Banding to map the specific
altera ons to known sites in the genome. Our data indicate that cells from IBC pa ents have higher levels of gene c
Figure 1. Selected characteris cs of the Inflammatory Breast Cancer pa ents seen at MD Anderson.
Table 1: Selected Studied Risk Factors
Probable risk factors Associa on *
Younger age at diagnosis +++
Younger age at menarche +
Younger age at live first birth +
High BMI (≥30) +++
Oral contracep ve use +
Ever pregnant +
Longer dura on of breast feeding +
White vs. African American ethnicity +++
Hormone receptor status (nega ve) +
Residence in Northern African countries +
*+++Indicates rela ve risk >3; + rela ve risk >1 and <3
14
altera ons/cell. In addi on, the frequency of
specific chromosome losses involving
chromosome 1,3, 8 and 17 was significantly higher
in IBC pa ents as compared to non‐IBC pa ents,
sugges ng that chromosome damage in IBC is non
‐random event involving specific chromosomes
that contain fragile sites and genes crucial to
carcinogenesis.
In addi on, among the triple nega ve IBC pa ents,
the accumulated gene c altera ons/cell were
found to be significantly higher than in non‐triple
nega ve pa ents.
B M O N T. U , MD, P D
IBC Database
The goal of the IBC clinical database is to develop an understanding of the natural history and the biology of
inflammatory breast cancer and to determine the poten al role of Sta n.
Since last October we have generated an IBC clinical database for all IBC pa ents and we also conducted a
retrospec ve chart review of pa ents diagnosed with inflammatory breast cancer from 1970 to 2011 and those that
received treatment at MD Anderson Cancer Center.
Objec ves:
Determine the IBC long term natural history
Defining the molecular subtypes in IBC
Determine whether mul disciplinary treatments are effec ve in IBC
Determine whether sta n reduces the recurrence of primary IBC
Total number of IBC pa ents iden fied: 1214 (including 240 stage IV pa ents)
Preliminary results indicate that IBC shows poorer prognosis. IBC stage III pa ents have 5‐year overall survival rates of
less than 50%, and 10‐year overall survival rates of less than 40%. In stage IV pa ents, the 5‐year overall survival rate is
less than 30%.
For this review, we defined mul disciplinary treatment as performing all of the following treatments—neoadjuvant
therapy, surgery and radia on therapy—and in this specific order. We hypothesized that mul disciplinary treatment
improves clinical outcome of IBC pa ents. The result showed that mul disciplinary treatment is more effec ve when to
compared to other treatment models such as surgery first or radia on therapy prior to surgery. Further, pa ents who
never underwent surgery showed the poorest outcome. In the Stage IV popula on, undergoing surgery was associated
with a good prognosis. TNBC subtype bore the strongest benefit from mul disciplinary treatment.
Further, we hypothesized that sta n reduces inflammatory reac ons in the body and possibly reduces recurrence risk
in IBC. There is some evidence that circula ng inflammatory markers such as acute phase proteins and IL‐6 increase
risk of recurrence and mortality. There are 993 primary IBC pa ents in the database and of those, 109 pa ents were
Figure 2: Distribu on of gene c damage endpoints among IBC cases and controls
P<0.001
3
5
8
4
15
using sta n. We defined sta n users as pa ents that have been prescribed sta n at least once. The primary endpoint
for our review was disease free survival (DFS) and the secondary endpoint was overall survival (OS). The median follow
up me was 39.2 months for sta n users and 31.4 months for non‐sta n users. Both showed that sta n use was
associated with improved DFS and OS.
From the result of our retrospec ve study into the role of sta n in IBC, we plan to conduct a prospec ve randomized
clinical study (See Figure 3).
Iden fying IBC targets (PA11‐1129: Iden fy the targets)
This project has mul ple objec ves as we seek to iden fy unique IBC‐targets that we enable us to be er address the disease. There are among 50 candidate genes.
Objec ves: To determine the clinical characteris cs in pa ents with IBC
To determine the correla on among biomarkers including ER, PR, HER‐2/neu as well as other candidate markers such as Ki67,p53,E‐cadherin,EGFR, CK5/6, IGF‐1/PDGF, RhoC GTPase, WISP3,CXCR4 and VEGFR1,2,3 and so on. To determine the correla on between clinical parameters and clinical outcomes such as local recurrence rates, distant metastasis free survival (DMFS), and overall survival (OS), and also whether the candidate makers have any independent prognosis under breast cancer subtype in IBC.
We brushed up the IBC clinical database at MD Anderson and collaborated with Dr. Savitri Krishnamurthy to collect
pa ent ssue samples. Using these samples, we are planning to examine the candidate genes that have poten al as
prognos c markers and treatment targets for IBC using IHC tes ng, RPPA, and mRNA arrays.
IBC mRNA project
Using the world consor um IBC mRNA data, we tried to iden fy the triple‐nega ve breast cancer (TNBC) subgroups
(Table 2). This project was presented at ASCO and the manuscript is being submi ed to peer‐reviewed journal.
Results: We found 7 subtypes for both Triple nega ve (TN)‐IBC and TN‐non‐IBC. While the correspondence between
our findings and those of Lehmann et al. was not perfect, there was a very significant correla on (P<2.2x10‐16). We
found no associa on between TNBC subtype and IBC status (P=.5023). As expected, we found that pa ents with IBC
had significantly worse recurrence‐free survival (RFS) than a comparison cohort of pa ents with advanced non‐IBC that
included not only pa ents with TNBC but also pa ents with ER‐posi ve and HER2‐amplified tumors (P=.0054).
However, TNBC subtype did not predict RFS. IBC status was not a significant predictor of RFS or overall survival in the
TNBC cohort. Conclusions: Both TN‐IBC and TN‐non‐IBC are heterogeneous. TNBC subtypes are unrelated to IBC
status. TN‐IBC and TN‐non‐IBC have the same subtypes and clinical outcome.
Figure 3. Clinical trial design for study of role of sta n in IBC
16
ER (+) IBC project
Using the world consor um IBC mRNA data, we detected 97
different genes between IBC ER (+) and non‐IBC state matched
ER (+) subgroup. Based on this informa on, we then
hypothesized that hormonal IBC‐specific gene signatures can
predict the poor prognosis of non‐IBC ER (+) breast cancer.
There are 97 different genes between IBC ER (+) and non‐IBC
state matched ER (+) subgroup. Using these gene signatures,
we performed the cross valida on of whether we could predict
IBC status. Result showed that we could iden fy the IBC status
using these gene signatures (all 4 models could iden fy the IBC
status). However, we do not know the exact biological meaning
of these 97 different genes or whether IBC ER (+) group has specific biology in comparison to non‐IBC ER (+) group.
Clinically, IBC ER (+) group showed poorer prognosis than non‐IBC ER (+) group. Thus, there is a possibility that this gene
signature may reflect the aggressive nature of any breast cancer. Therefore, we hypothesize that the gene signature
may predict the poor prognosis group in non‐IBC ER (+) popula on.
Resource used: There are 3 public breast cancer mRNA databases.
Transbig (n=198. ER (+) n=124) Marinz
(n=200. ER (+) n=155) Wang (n=286. ER (+)
n=178)
These popula ons did not receive any
systemic cancer treatments except
surgery. Therefore, we can examine the
natural history of ER (+) BC popula on.
TIG1 Project Report
Inflammatory breast cancer (IBC) is the
most lethal and aggressive form of breast
cancer. The molecular mechanisms for the
tumorigenic and metasta c proper es of
IBC are largely unknown. In this study, we
show that high expression of tazarotene‐
induced gene 1 (TIG1) significantly
correlated with shorter survival of
pa ents with IBC and demonstrate that
TIG1 mediated cell prolifera on,
migra on, and invasion of IBC cells in vitro
and tumor growth of IBC cells in a
xenogra animal model. We also
iden fied receptor tyrosine kinase Axl as a
func onal partner of TIG1. Our data
Table 2. Subtypes of triple nega ve IBC and non‐IBC breast cancers.
Figure 4. (A) High TIG1 expression was significantly associated with reduced pa ent survival
dura on. (B) Silencing TIG1 reduced prolifera on of IBC cells. © Silencing TIG1 inhibited
tumor growth in a xenogra model. (D) Silencing TIG1 reduced invasion of IBC cells. (E) TIG1
knockdown decreased the expression of Axl in IBC cells. (F) TIG1 interacted with Axl in IBC
cells. (G) Ectopic expression of TIG1 increased the protein level of Axl.
17
showed that TIG1 interacted with and stabilized Axl by inhibi ng its proteasome‐dependent degrada on. Indeed, Axl
expression posi vely correlated with TIG1 expression in IBC human ssues. Last, we show that TIG1 deple on in IBC
cells decreased Axl expression and inac vated NF‐κB, which led to downregula on of MMP‐9, indica ng that TIG1
regulates invasion of IBC cells through media on of the Axl signaling pathway. Taken together, our results link a novel
tumorigenic gene, TIG1, to the key tumorigenic gene Axl in IBC. Further studies are needed to confirm that TIG1 is a
promising IBC‐specific therapeu c target in the treatment of pa ents with IBC.
S O A L , MD Our group is focused on improving outcomes for IBC pa ents through: Outstanding surgical care of the IBC pa ent
We have shown that our local‐regional control rates for IBC here at MDA are at 90%, which is a significant
improvement over previously published reports from other ins tu ons. (see J Clin Oncol 30, 2012 (suppl; abstr 1102)
Development of novel surgical protocols to minimize morbidity for IBC pa ents
We have launched a protocol to assess PET and US
imaging of the axilla before and a er neoadjuvant
chemotherapy to determine which IBC pa ents can
safely forego axillary lymph node removal. The data
from this study should significantly improve lymphedema
rates in IBC pa ents.
Study of disseminated (bone marrow) and circula ng
(blood) tumor cells in IBC pa ents
We published a report in the Lancet Oncology in 2012
(Jul;13(7):688‐95) demonstra ng that presence of
circula ng tumor cells predicted decreased relapse‐free
and overall survival in breast cancer pa ents. This model
is concurrently being tested in IBC pa ents, and the
preliminary data is highly significant (See Figure 5). We
plan to use this informa on to assess response to novel
therapies for IBC in the near future.
Iden fica on of novel targets on disseminated and circula ng
tumor cells in IBC
We have developed a microfluidic chip system to assess CTCs in
IBC pa ents. This system allows us to perform FISH analysis on
captured CTCs, and then document and morphologically evaluate
the CTCs that have amplifica on of HER2 (see Figure 6a & b).
Interes ngly, we found that a significant number of pa ents with
HER2 nega ve primary tumors had HER2‐amplified CTCs. We hope
to use this informa on for novel treatments of HER2‐nega ve
pa ents with IBC with an ‐HER2 agents. This data was presented
Figure 5. Circula ng tumor cells and RFS in IBC pa ents CTC = Number of Circula ng Tumor Cells, OS = Overall Survival P = 0.0022
Figure 6a: Illustra on of a CK + and CD45‐ CTC. Note the Numerous orange signals indica ng increased copy num‐bers of HER2. The primary tumor was nega ve for HER2 gene amplifica on.
18
at ASCO 2012 (J Clin Oncol 30, 2012 (suppl; abstr TPS10631), and is
now submi ed for publica on.
Assessment of the role of the CXCR4/SDF‐1 axis in IBC and
development of novel targets for metastasis preven on
We published two reports evalua ng a novel CXCR4 inhibitor,
including one in a xenogra mouse model of IBC (Clin Exp
Metastasis. 2010 Apr;27(4):233‐40). We are now embarking on a
collabora ve project with Dr. Steven Millward to determine if
tyrosine sulfa on of CXCR4 (which significantly enhances
enhanced affinity for its ligand SDF‐1) results in enhanced growth,
migratory signaling, and increased metasta c poten al of IBC
cells.
Development of a novel predic ve in vitro assay for an ‐cancer drug selec on
We selected a rare subpopula on (0.01%) of SUM149 cells (triple‐nega ve IBC subtype) which is capable of surviving
body‐like metabolic challenges (lack of Gln, Glc). These cells are highly adaptable, anchorage‐independent, resistant to
doxorubicin, paclitaxel, celecoxib, etc., and metasta c in nude mice. This work was published in 2012 in PLoS One (7
(5):e36510. Epub 2012 May 3). We plan to use this model to develop cancer subtype‐specific in vitro models for
evalua ng new therapies against IBC. Op mally, we will u lize FDA‐approved drugs to speed implementa on into the
clinic, and align these in vitro models with clinical IBC studies.
R O S C B W W , MD, P D
Many lines of evidence implicated IBC as a disease of stem cells. It is enriched for triple nega ve breast cancers which
are less differen ated cancers. It is associated with high rates of metastasis and recurrence believed to be mediated by
cancer stem cells. Stem cell markers such as ALDH1 and EZH2 are prognos c in IBC pa ent outcomes. All gene
expression signatures developed from mammary gland stem cells are expressed in IBC pa ent samples. For this reason
understanding and targe ng stem cell biology is a cri cal core in the IBC research program.
Our core has several major projects dedicated to changing outcomes in IBC through understanding stem cell biology.
First, IBC is characterized by radia on resistance with high rates of local failure a er radia on therapy. While
aggressive radia on treatment regimens have been successful, a radiosensi zing agent to promote be er outcomes
with less toxicity is highly desirable. Our screening program has developed a stem cell specific radia on resistance
screen through which we have a top promising radiosensi zer to take forward in clinical trials. Specifically, laboratory
and clinical data suggests sta n use radiosensi zes IBC stem cells. We are ac vely pursuing addi onal studies to
elucidate the mechanism of this effect. In addi on, we have iden fied several dietary flavonoids that target IBC stem
cells though inhibi on of b‐catenin in breast cancer stem cells. Second, while stem cell targe ng agents are needed, it
is cri cal we understand the plas city of breast cancer stem cells to design successful clinical trials. We have
demonstrated that commonly used medica ons that inhibit histone deacetylase and appear to target cancer cells can
promote stem cell proper es from single non‐stem like cells. These data highlight the cri cal need to assess therapies
for their impact on cancer cell subpopula ons and demonstrate the need for be er assays of response in
micrometasta c disease. Finally, without clear evidence for IBC specific biology in numerous studies of the tumor cells
from IBC pa ents, we are examining differences in the breast ssues of pa ents that develop IBC and demonstra ng
the effects of normal cells on IBC tumor progression. Specifically, we have demonstrated for the first me that IBC skin
Figure 6b: Illustra on of a disseminated tumor cell (DTC) in bone marrow showing increased copy numbers of HER2 as evidenced by increased orange signals. The primary tumor was nega ve for HER2 gene amplifica on.
19
invasion is promoted by
normal cells from the
bone marrow,
mesenchymal stem cells
through an EGFR
targeted mechanism.
Further, the normal
breast in IBC pa ents is
dis nct from non‐IBC
pa ents with spa ally
dis nct stem cells
throughout the normal
ssues, and infiltra ng
immune cells that can
been picked up in
biopsies even prior to
the diagnosis of IBC. We
are working to
demonstrate the
rela onship between
stem cells,
mesenchymal stem cells
and immune cells in
preparing the breast to
mediate the IBC
phenotype and propose
novel treatment of the
normal ssue may lead
to be er preven on
and treatment.
In conclusion, great progress has been made in preven on, basic research, radiosensi zers and stem cell plas city
leading to two upcoming trials for stage III and stage IV IBC pa ents. Our work has demonstrated the importance of the
microenvironment in media ng the IBC phenotype and opened the door to greatly expanding targets for treatment and
preven on.
P S K , MD
Our group is focused on addressing all pathology related issues for the Morgan Welch Inflammatory Breast Cancer
Research Program and Clinic.
Clinical Care:
We have provided highest quality of pa ent care related to pathology work up of pa ents seen in the IBC clinic. This
includes providing the basic ssue diagnosis and expedi ng the work up of the prognos c and predic ve markers of
Figure 7. A‐ Preven on of IBC: Studying the normal ssue adjacent to cancers is revealing clues as to what changes occur prior to the cancer that may contribute to the IBC phenotype. Significant differences are appreciated in the spa al distribu on of stem cells and in the infiltrate of immune cells such as macrophages. Le image is Bx 10 years prior to Dx BMI 23.5 and Right image is Bx 10 years prior to Dx BMI 35.5. B‐ Basic Research in IBC: comparing IBC and non‐IBC cells lines cultures in stem cell promo ng culture vs. standard culture revealed miRNA that are differen ally expressed in IBC. These targets are being studied to develop therapeu c strategies and to understand the unique biology of IBC. C – New Therapies: SUM149 treated in 2D cultures (le ) and stem cell promo ng 3D cultures (right) reveal a drama c sensi za on of stem cells with the use of sta ns. In IBC pa ents on sta ns the risk of local failure a er radia on was reduced more than half. D. IBC is a disease of stem cells and our work clearly demonstrates that the stem cell state is in equilibrium with differen ated cells. Harnessing this equilibrium we are using HDAC inhibi on to halt destruc ve differen ated cells in metastases and promote quiescent stem cells to improve outcome.
A ‐ Prevention
C ‐ New radiosensitizers D ‐ Clinical trials
10 yrs
• Tissue macrophages are elevated in normal breast tissue of IBC patients and are present 10 years prior to developing cancer
B ‐ Basic research
• Overexpression of miR‐200 family in IBC vs. aggressive, non‐IBC cell lines validated with qPCR
• miR‐200 targets Zeb1/Zeb2, E‐cadherinvalidated in IBC vs. aggressive, non‐IBC cell lines
• 81% of IBC patients in MDA cohort are overweight or obese
•Obesity is associated with tissue inflammation
Parameter Estimate SE p‐value HR 95% HR CI
TNBC Non‐TNBC vs
TNBC
‐0.98 0.23 <.0001 0.37 0.24 0.58
LVI NEG vs POS ‐0.84 0.25 0.001 0.43 0.26 0.70
PCR CR vs Non‐CR ‐1.42 0.52 0.01 0.24 0.09 0.67
Statin 1 vs 0 ‐0.86 0.40 0.03 0.42 0.19 0.92
Dose (Gy)
0 2 4 6
Su
rviv
ing
Fra
ctio
n
0.01
0.10
1.00
10.00
Dose (Gy)
0 2 4 6
Su
rviv
ing
Fra
ctio
n
0.01
0.10
1.00
Statin
No Statin
Statin
No Statin
Tumor Subtype
IBC
(n=141) BMI
ER+ 29% 32.6
ER/Her2 + 18% 30.6
Her2+ 22% 30.7
Triple Negative 31% 31.1
+/‐ VA
• HDAC inhibitorsreprogram breast cancer stem cells
• A clinical trial to test HDAC inhibitors in patients with metastatic pleural effusions is funded by the IBC network .
Vehicle
1mM V
A
M SAHA
1
0
20
40
60
80
% o
f cel
ls in
pha
se
G0/G1S-phaseG2/M
20
any type of specimens
obtained from IBC pa ents
such as core biopsy, skin
punch biopsy and
mastectomy.
Tissue Registry:
We have played a key role in the maintenance and opera on of the IBC ssue registry which forms a key resource for all current and future research related to IBC. We established the standard of opera ons for ssue collec on and storage
of ssues in the IBC ssue registry including collec on of frozen ssue (snap frozen), op mal cu ng medium (OCT) frozen , RNALater and formalin fixed and paraffin embedded ssue of breast core biopsy,
skin punch biopsy and mastectomy specimens of pa ents with IBC. In addi on to crea ng the ssue resources, we are also involved with quality assurance and disbursal of high quality ssue for research of IBC. The quality assurance of the collected ssues forms a key component to establishing the tumor cellularity of the collected ssue and ensuring the presence of invasive tumor as collected IBC ssue may have only intraductal carcinoma or lymphovascular tumor emboli. Moreover, we have developed an addi onal resource of collec ng paraffin blocks in pa ents who underwent surgery outside of MD Anderson as cohort II of the registry protocol.
We have created ssue microarrays of pre‐chemotherapy and post‐chemotherapy ssues which forms an important resource for protein expression and biomarker research of IBC.
Ongoing Work:
We are ac vely studying to understand all the issues related to bio‐banking of IBC pre‐chemotherapy ssues. This would add immense value to selec ng op mal quality assured ssue for genomics and proteomics projects from the available ssue in the registry for obtaining key answers for the dis nc on of IBC from non‐IBC.
We are inves ga ng poten al modali es such as op cal imaging for immediate assessment of the core biopsies to improve our ability to collect high quality ssue with op mal cellularity.
We are working to understand all pathology related issues of IBC, in par cular, methods to ascertain residual burden of disease in a more accurate and reproducible fashion.
We are ac vely crea ng resources to test and validate poten al biomarkers of interest iden fied by genomics and proteomics projects on frozen and fixed ssues to iden fy markers that can be useful for diagnosis, treatment and response to therapy of IBC.
8a, b, c. Examples of frozen sec ons of core biopsy of inflammatory breast cancer.
8d. Example of invasive tumor with patchy distribu on, demonstra ng challenge of bio‐banking
inflammatory beast cancer.
a b
c d
21
I H J R , P D
IBC is a rare and aggressive
breast cancer whose e ology is
unknown and gene c profiling
has not iden fied differences
between IBC and non‐IBC. Earlier
work by others has suggested
that viruses in par cular, the
Mouse Mammary Tumor Virus
MMTV), may play a role in the
e logy of IBC. As viruses are
known to induce an immune
response by the host, Dr. Hui Gao
(Research Scien st) studied the
immunology of IBC and non‐IBC
pa ents. Her ini al studies have
iden fied that IBC pa ents have
lower total leukocytes (WBC) and
lower CD4+ T‐helper lymphocytes
(Fig 9a).
In addi on to cellular immunophenotypes and func on, Evan N. Cohen (Pre‐doctoral Candidate)
assessed the presence of inflammatory proteins in the serum of IBC and non‐IBC pa ents. He showed that IBC pa ents
have increased levels of inflammatory cytokines (IL‐1, IL‐6, and TNF‐a) and chemokines such as MIP‐1a and IL‐8,
compared with levels in sera of non‐IBC pa ents (Fig 9b). In the next year, we propose to iden fy a cytokine/
chemokine profile that is unique to IBC pa ents.
Circula ng Tumor Cells (CTC) is a major area of interest in my laboratory. Antonio Giordano, MD, PhD (Visi ng Scien st
from the University of Naples “Federico II”, Naples, Italy) and Dr. Hui Gao have been studying the predic ve and
prognos c values of CTC in breast cancer. Dr. Giordano has shown that although CTCs with an epithelial phenotype are
not very prognos c in pa ents with HER2 over amplifica on, CTC undergoing EMT (EMT‐CTC) are predic ve of clinical
outcome (Fig 9c). Dr. Giordano received the ASCO 2012 Young Inves gator Award from Conquer Cancer
Founda on and the 2012 AACR‐Bristol‐Myers Squibb Oncology Fellowship in Clinical Cancer Research awards to
expand his ini al work on CTCs.
Finally, because the limited availability of ssue from IBC pa ents, we are working on serum biomarkers that will allow
repeated sampling for diagnosis as well as for the monitoring of pa ents on therapy. Simone Anfossi (Pre‐doctoral
Candidate) has been working on the isola on and profiling of microRNA (miRNA) in sera of breast cancer pa ents (Fig
9d). He has iden fied one miRNA, miR‐19a, that differen ates metasta c pa ents from those with locally advanced
disease and is able to differen ate between HER2+ and Her2‐ metasta c IBC pa ents. Current work is underway to
establish a miRNA profile for IBC and non‐IBC pa ents.
These studies would not have been possible without the support and dedica on of our pa ents, support laboratory
personnel (Sanda Tin, Qiong Wu and Raul Josh Garza), clinical personnel (physicians, nurses and research), and funding
from the Morgan Welch IBC Research Program and Clinic through the Texas Rare Disease Grant.
22
B M O —R C B , P D
Pa ents with TNBC are nega ve for
estrogen receptor, progesterone
receptor, and low for HER2 expression,
and have poor prognoses because tumors
o en metastasize, leading to death.
Preven ng metastasis as well as inhibi ng
the tumor growth, is crucial to improving
the prognosis of TNBC. We previously
showed that pa ents with ERK2‐
overexpressing TNBC were at higher risk
of death than those with low‐ERK2‐
expressing tumors. The MEK‐ERK pathway
has not been explored as a poten al
therapeu c target of TNBC metastasis.
Interes ngly, when we treated the TNBC
cells lines with the MEK1/2 ATP
uncompe ve kinase inhibitor
(selume nib), it did not reduce cell
viability in a two‐dimensional (2D) cell
culture. However, in a three‐dimensional
(3D) cell culture model, selume nib
changed the mesenchymal phenotype of
TNBC to an epithelial phenotype. Cells
undergoing epithelial‐mesenchymal
transi on are well known to poten ally
contribute to the metasta c process and have increased ability to form mammospheres. Based on these observa ons,
we tested the hypothesis that targeted inhibi on of the MEK‐ERK pathway by selume nib prevents lung metastasis in
TNBC.
Next, TNBC cell lines treated with selume nib, showed inhibi on of anchorage‐independent growth, an indicator of in
vivo tumorigenicity (P<0.005), decreased CD44+CD24‐/low (breast cancer stem cells) expression, aldefluor ac vity and
mammosphere forming efficiency. Most importantly, mice treated with selume nib formed significantly fewer lung
metastases than did control mice injected with a vehicle (P<0.05, 2‐sided t test.) Our data shows that the MEK inhibitor
can inhibit breast cancer stem cells sugges ng that our findings have clinical implica ons for the use of MEK inhibitors
in the preven on of metastasis.
S O —R B S , P D
Tackling Tumor Heterogeneity to Develop Combina on Therapies for IBC
An aggressive disease like IBC is characterized by a tremendous cellular heterogeneity, which poses serious difficul es
in therapy development. How do we choose therapies out of hundreds of available drugs that have been developed
against a variety of “therapeu c targets”, which will be effec ve against the heterogeneous disease? To address this
problem, we have decided to focus on the most adaptable subpopula on of cancer cells. We have evidence that in
Figure 10. The MEK inhibitor selume nib (AZD6244 – ARRY‐142886) prevents lung
metastasis in a triple‐nega ve breast cancer (TNBC) xenogra model. A, Effect of selume nib on cell prolifera on was assessed by WST‐1 assay and both TNBC (MDA‐MB‐231 and SUM‐149) cells were resistant to selume nib. B, so agar colony forma on of TNBC cells treated with selume nib exhibited significant inhibi on of anchorage‐independent growth, an indicator of in vivo tumorigenicity C, TNBC cells grown in a 3D‐cell
culture treated with selume nib changed from a mesenchymal phenotype to an epithelial phenotype. D, mammosphere forma on presented as the average number of spheres per 20,000 and 5,000 cells plated was reduced a er treatment with selume nib E, TNBC xenogra model established with MDA‐MB‐231–LM2‐4175 was treated with selume nib showed significantly fewer lung metastases than did mice injected with a vehicle.
MDA-MB-231
0
20
40
60
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100
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1 10 1000.10.010
20
40
60
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100
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23
vitro selec on for metabolic adaptability selects rare
(<0.01% in popula on) cancer cells present in SUM149
cell line (triple‐nega ve IBC) that are highly tumorigenic
and metasta c in nude mice. We observed metastases to
lungs, liver, brain, and skin (Singh et al., PLoS ONE, 2012).
Our study revealed a linkage between metabolic
adaptability and structural adaptability in metasta c
cancer cells, which can be exploited for tackling tumor
heterogeneity in IBC.
B M O —R B L. E , P D
Inherent receptor/ligand interac ons
that can occur on the surface of
tumor cells can act as a dynamic
molecular address that can enable
targeted delivery of drugs and
imaging agents to tumors (Arap et al.,
2004). We hypothesize that such
molecular addresses exist within
inflammatory breast cancer (IBC), and
can be exploited for ligand‐based
imaging and early detec on. To this
end, we have devised two research
arms that will concurrently
characterize the receptor/ligand
interac ons within IBC via pep de‐
based phage display. The first
research arm will u lize a
combinatorial pep de library
(consis ng of more than 1x1010
unique 7‐mer or 8‐mer pep des) to
epitope‐map the circula ng pool of
human an bodies elicited against
tumors in IBC pa ents. Using 454‐
based sequencing, we will be able to
rapidly iden fy thousands of pep de
mo fs from mul ple IBC pa ent
samples, in an a empt to iden fy
those pep des that reflect tumor‐
associated an gens within this
disease. Our second approach characterizes a known receptor target (glucose regula ng protein‐78, GRP78) expressed
on breast tumor cells, including IBC (Figure 12). To date, we have characterized a pep de (WIFPWIQL, amino acid
sequence) that specifically binds GRP78 protein and are currently tes ng the efficacy of this pep de to target GRP78
expressing IBC tumors in vitro and in vivo (see Figure 13).
Figure 12. Expression of GRP78 is elevated during progression of human IBC. GRP78 expres‐
sion was detected by immunohistochemistry in primary (le panel) and secondary (right
panel) IBC tumors. Tumor‐free lymph nodes (middle panel) displayed minor expression of
GRP78 in the germinal center. Right panel inset, metastasis‐posi ve lymph node stained with
an isotype an body control.
Figure 13. The GRP78 homing pep de, WIFPWIQL, mediates cell binding, internaliza on and
homing towards IBC cells. A) Phage displaying the WIFPWIQL pep de (compared to no pep de
control, Fd‐tet) bound to IBC cells and metasta c breast cancer cells with high affinity compared
to non‐IBC cells. B) Cell viability was assessed using a WST‐1 assay on 4T1.2 cancer cells following
16 hours treatment with BMTP78 (a WIFPWIQL‐pep de drug conjugate). BMTP78 killed aggres‐
sive breast cancer cells in a dose defendant manner, which could be abrogated in the presence of
a GRP78 neutralizing an body.
Figure 11. Selec on of
metabolically adaptable
subpopula on of IBC cells. We
plated 0.5 million SUM149
cells in a culture medium
lacking glutamine. The rare
cells that survived and
proliferated to yield colonies
in 5 weeks were stained with
crystal violet dye.
24
T he Morgan Welch IBC Research Program and Clinic is conscious of the importance of spreading awareness
and understanding of inflammatory breast cancer and our unique role to lead the dialogue with pa ents,
healthcare professionals and the general public. It is through outreach and social media that we are able to advocate
for learning of disease symptoms and presenta on and the appropriate mul ‐modality treatment approach for
pa ents. Moreover, it is an opportunity for us to disseminate new knowledge from research so that pa ents, family
and healthcare providers are apprised of the latest findings. Ul mately, outreach grants us the occasion to be in touch
with the humanity of the disease, to be with and work with the pa ents and the people we are figh ng for everyday.
F . /
In September of 2011, we launched the Morgan Welch IBC Program Facebook page to engage pa ents and the
community in a dialogue of all things inflammatory breast cancer. Through our page we have shared our posi on
regarding the value of a mul ‐disciplinary team approach
to IBC care and the latest breaking research news in
breast cancer. Our Facebook wall has been a place for
pa ents to ask ques ons and get answers from the
experts. Moderated by Dr. Naoto Ueno, Dr. Wendy
Woodward, Danielle Walsh (Program Manager) and
Summer Jackson (Clinical Studies Coordinator), the page
has grown to more than 600 likes. In FY12 alone, our
content was seen by more than 28,000 people through
individuals visi ng our page or seeing our posts through
sharing. Our total daily impressions for any content
associated with our page was 551,137 impressions. The
demographics for our followers include both men and
women ages 18 to >65 years, with a majority being
women between the ages of 35‐54. Moreover, our reach
is interna onal, with followers from 39 different
countries. Facebook has provided a dynamic forum for us
to exchange ideas and best prac ces, acknowledge our
Program’s and others’ achievements , and to engage in
conversa on with our pa ents, advocates and others in
the health care community. It will con nue to be a
valuable resource for the program.
Program Outreach
25
T . /
Prior to our Facebook page launch, the Morgan Welch IBC
Program joined Twi er, a real‐ me informa on network known
for short, 140‐character tweets of informa on. This unique social
media tool fosters dynamic exchanges of informa on that have
the poten al to spread exponen ally across the Twi er
community. We use Twi er in mul ple ways—as a direct outlet
for Facebook updates, to share commentary or the latest news as
it breaks, to promote open clinical trials, and to engage pa ents,
advocates and other health care professionals in dialogue. To this
end, we established and registered #ThinkIBC as an official
healthcare hashtag to facilitate conversa ons and informa on
about inflammatory breast cancer. Twi er has been a powerful
resource for reinforcing the MD Anderson brand and for
marke ng our unique program. We share tweets from other MD
Anderson programs including Physician Rela ons, Professional
Oncology Educa on, and Cancer Frontline and from individual
faculty experts, fostering the spirit of community and
collabora on. With each tweet, retweet and reply, the Morgan
Welch IBC Program is building and strengthening rela onships
with those we serve.
5 A C
October 2011 marked the fi h anniversary of the opening of the Morgan Welch IBC
Clinic at MD Anderson, the first mul ‐disciplinary clinic in the world dedicated to this
rare disease. To honor this occasion, we shared a series called “5 for 5” via Facebook
and email to highlight program accomplishments over the past five years. Weekly in
October, members of the program cited what they believed to be our top five
accomplishments. Jie Willey, Administra ve Director of Protocol Research, shared
these top five:
1. Leading center for Interna onal Tissue and Serum Registry for IBC.
2. Great communica on and team effort towards transla onal and clinical research in
IBC.
3. Large clinical trial por olio focused on IBC.
4. Willingness of our graceful pa ents to volunteer to par cipate in IBC clinical trials.
5. Dedicated research staff and inves gators conduc ng IBC clinical trials.
In apprecia on for all who founded our program and helped us to build our program
over the past five years, we hosted a celebra on of thanks at Treebeards in downtown
Houston. The event was a ended by Program faculty, staff and our dearest friends
and advocates from all over the country. Execu ve Director Naoto Ueno gave remarks
and Danielle Walsh read from a le er sent by Massimo Cristofanilli, both applauding
our efforts and mo va ng all to con nue our work on behalf of our pa ents.
26
We also hosted a more in mate IBC Ambassador Luncheon as an
expression of thanks to the individuals who contribute me and
effort to promo ng the Morgan Welch Program and our research in
the community. A slide presenta on reflected the five years of
Program history and the memories that have been made thus far. Dr.
Naoto T. Ueno, Execu ve Director was the speaker and we were
treated to guest appearances by Dr. Ronald DePinho, MD Anderson
President, Dr. Tom Buccholz, Division Chair‐Radiology and Special
Advisor to the IBC Program and Dr. Gabriel Hortobagyi, Department
Chair ‐ Breast Medical Oncology. Asfaneh Keyhani, IBC Lab Manager,
took interested guests on a tour of our mul ‐disciplinary laboratory.
P R P
The Morgan Welch IBC Program sponsored a pink ribbon
in the Breast Health Collabora ve of Texas’ Pink Ribbon
Parade, a public event meant to raise awareness of breast
cancer. The design of our one‐of‐a‐kind ribbon honoring
pa ents with IBC was commissioned to local Houston
ar st Liz Conces Spencer. Ribbons made their debut at a
kick‐off party in front of City Hall in Houston with Mayor
Anise Parker and other Parade sponsors including Pink
Ribbons Project, Baylor College of Medicine, and The
Rose. The ribbon sculptures then paraded around
Houston‐area October Breast Cancer Awareness events
and were seen at Tour de Pink and the Susan G. Komen
Race for the Cure.
O I B C A M
Earlier in the year, the State of Texas declared October 2011 as Inflammatory Breast
Cancer Awareness Month and as such, the Morgan Welch IBC Program sought to
ac vely bring awareness to our cause. We hosted IBC informa on booths at the
Breast Health Summit in Houston and at Alvin Octoberfest at Alvin Lutheran Church.
Program members and advocates represented our group in teams at Susan G. Komen
–Houston Race for the Cure, the 3rd Annual TeamKaren 5K and Fun Run, and IBC
Network Founda on’s Hunt for Hope. In conjunc on with the 94.5 The Buzz’s Rod
Ryan Show’s Boobs Rock events benefi ng MD Anderson, we handed out IBC
literature and free gi s to more than 300 people and Danielle Walsh was invited to
represent Dr. Anthony Lucci in on‐air interview with the popular morning radio show.
Finally, we were honored to a end the annual Zeta Tau Alpha Think Pink! Luncheon
suppor ng our Zeta Tau Alpha Houston Alumnae Associa on Fellowship Award in
IBC.
The Morgan Welch IBC Program steadfastly seeks opportuni es to educate and empower pa ents, healthcare providers
and the general public with the knowledge and understanding of IBC. By partnering with the community, we can
enhance the future for all IBC pa ents.
27
Note of Appreciation
28
T 713‐745‐2087 F 713‐563‐0905 The University of Texas MD Anderson Cancer Center
Department of Breast Medical Oncology 1515 Holcombe Blvd, Unit 1354, CPB5.3434
Houston, TX 77030
www.mdanderson.org/IBCProgram
www.facebook.com/InflammatoryBreastCancer
www.twi er.com/inflammatoryBCa
